Future of Monoclonal Antibody Therapy in Parkinson’s Disease

Recently in the New England Journal of Medicine (NEJM), two-phase, two promising trials, Phase 2 Trial of Anti-alpha-Synuclein Antibody in Early Parkinson’s Disease (PASADENA) and SPARK, were published.1^, 2 Two monoclonal antibodies (mAbs), Prasenizumab and Cinpanemab, directed at aggregated alpha-synuclein (α-synuclein) were investigated as Parkinson’s disease-modifying therapies with a similar primary endpoint (baseline changes in the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] total score). They also had a similar neuroimaging secondary endpoint, i.e., single-photon-emission computed tomography (SPECT).1^, 2

Parkinson’s disease (PD) is a progressive neurological condition for which there is no recognized treatment, but there are therapies available to provide symptom relief and maintain quality of life. The goal of the PD clinical studies should be to delay the development of motor problems that could lead to long-term difficulties. Finding new multitarget therapies with minimal side effects is a serious challenge, nevertheless, given the dramatic increase in PD incidence rates across the world.3

Lewy bodies and Lewy neurites both contain significant amounts of the protein α-synuclein. The cytoplasmic protein α-synuclein, which is small and natively unfolded and can misfold to form aggregated polymers, has been linked to the pathophysiology of PD. The α-synuclein protein is encoded by the synuclein alpha (SNCA) gene, and rare genetic mutations in this gene cause PD, which is inherited by the autosomal dominant mechanism.4^, 5 Studies on α-synuclein transgenic mice using monoclonal antibodies (passive immunotherapy) reveal that anti-synuclein antibodies with greater relative affinity to the C-terminus protein region moderated neuronal pathology by reducing intracellular accumulation of α-synuclein in cell bodies and synapses, designed to protect against synaptic loss and gliosis, and enhance motor and cognitive impairment.6^–8 Thus, the principal is based on the fact that Lewy body regulation and cell clearance mechanisms are mostly increased by anti-synuclein aggregation therapy.9

Looking at the encouraging results of monoclonal antibodies on mice, the researchers focused their attention on the human trials of different mAbs directed at α-synuclein. In a multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose, phase 1b study, a humanized immunoglobulin (Ig)G1 monoclonal antibody PRX002/RG7935 (PRX002), made to target the neurotoxic (aggregated) forms of α-synuclein of the C-terminus, was administered among mild-to-moderate PD patients over eight study sites in the United States. PRX002’s single and multiple doses both demonstrated high affinity binding of peripheral α-synuclein. Similarly, PRX002 had a dose-dependent increment in cerebrospinal fluid (CSF). Thus, mAbs found in CSF concentrations in the brain are thought to cause extracellular aggregation of α-synuclein. There were no reported fatalities, severe adverse effects (AEs), or anti-PRX002 antibodies. The phase 2 PASADENA trial was supported by the safety and tolerability profiles of all PRX002 tested dosage levels.10

The phase 2 trial results were highly awaited, and researchers were sure to unlock the treatment option of mAbs for PD with favorable results. However, the opposite happened. The phase 2 trial of PASADENA, a three-part, randomized controlled trial, examined the safety and efficacy of low-dose (1,500 mg) and high-dose (4,500 mg). The trial found that the one-year progression of the sum of scores on parts I, II, and III of the MDS-UPDRS had no significant difference when compared to placebo. Infusion reactions were the most commonly reported adverse events. Participants in the placebo group who were switched to Prasinezumab in part 2 (delayed-start cohort) compared to the early-start cohort did not notice an improvement in their MDS-UPDRS total scores or subscores. This showed that it is unlikely that Prasinezumab treatment for an additional 48 weeks would have any effect on symptoms. Prasinezumab therapy also showed no apparent effect on 123I-ioflupane SPECT imaging either.1

Another waited for the result of the trial was SPARK, which used Cinpanemab, a human-derived mAbs.2 Like the PASADENA trial, this trial did not support preclinical studies’ findings. Cinpanemab concentrations in the serum and CSF rose dose-dependently in a phase 1 study examining healthy volunteers and people with PD, with no evidence that anti-cinpanemab antibodies were formed. Similarly, there may be dose-dependent biologic activity in people with PD, based on the formation of cinpanemab—synuclein complexes in plasma.11

The cinpanemab’s effects on clinical indicators of disease development, such as the MDS-UPDRS and alterations in Dopamine Transporter SPECT imaging, throughout a 52-week period were similar when compared to the placebo group in the phase 2 SPARK trial, a continuation of the above phase 1 study.2 According to the results of these two trials, using an N-terminally targeted antibody as a monotherapy to target extracellular synuclein might not be sufficient to limit the progression of the disease.1^.2

In his editorial in the NEJM, Alan Whone reviewed the findings and posed two questions. The first was that preclinical research had given rise to false hope in the PD community, and the second was that type II errors were being produced by our current clinical trial designs, which prevented us from demonstrating disease modification in PD. The former reason is more plausible for PASADENA and the SPARK trial, but the latter explanation is still possible. This implies the need for more sophisticated outcome measures. The results, he added, were “more than disappointing and definitely had no implications for current practice’’.12

Now, the future mAbs trials pose a financial crisis as big pharma companies hesitate to fund the drug development with negative results. But, the sponsor of PASADENA has not been discouraged from starting a phase 2b trial despite the unfavorable results.12 While, Biogen announced that it will be discontinuing the development of Cinpanemab.13

Okun and Subramanian discussed the causes of the trial’s failure in a blog post on Parkinson Secrets. They questioned the accuracy of Lewy bodies as targets and the slow activity of α-synuclein aggregates in the pathogenic process. The trail flaws present were the failure to measure CSF as a biomarker and a lack of target engagement assessment. They also stated that Lewy body pathology, signifying the end of “functional α-synuclein,” needs to be addressed. According to Alberto Espay from the University of Cincinnati, Lewy pathology is composed of “tombstones of previously normal, monomeric soluble synuclein.” It is probably too late once proteins polymerize into Lewy bodies. This may help to clarify the cause(s) of the failure of monoclonal antibodies and upcoming vaccination research.14

According to the evidence, which appears to be conclusive in its entirety, monoclonal antibodies may no longer be used to treat early PD. We also expect that there is a fault in trial design, needing a more coherent and sophisticated trial design with outcomes measures of trial engagement for a longer duration. Thus, the pathway of monoclonal antibodies for PD is an uphill task with less supporting evidence and reduced financial interest from big pharma companies. However, excellence is a characteristic of human beings. Though it is a dead end, there is always an American land waiting to be discovered by Columbus.